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A 36-year-old man has an LDL-cholesterol of 190 mg/dL, normal triglycerides and HDL. His lipoprotein (a) is four times normal. His coronary calcium score was appropriate for a man of 60 years. He has no symptoms of coronary or peripheral vascular disease. Physical exam was normal except for a systolic aortic valve murmur. His mother had a myocardial infarction at age 51 and had no known risk factors other than an elevated cholesterol. He developed muscle symptoms with each of 3 statins (atorvastatin, rosuvastatin, and simvastatin) but levels of creatine kinase remained normal. On genetic analysis he was heterozygous for the SLCO1B1 mutation associated with statin myopathy, and for a loss of function mutation in the gene for the LDL receptor. His LDL-C goal is in the 40 to 50-mg/dL range because of his two lipoprotein risk factors, his coronary artery calcification, and his mother’s history of premature coronary artery disease. He has no other risk factors and his diet and exercise habits are excellent. How would you manage this patient?

Plasma lipids are transported in complexes called lipoproteins. Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemia or hyperlipidemia. Hyperlipemia denotes increased levels of triglycerides.

The major clinical sequelae of hyperlipidemia are acute pancreatitis and atherosclerosis. The former occurs in patients with marked hyperlipemia. Control of triglycerides can prevent recurrent attacks of this life-threatening disease.

Atherosclerosis is the leading cause of death for both genders in the USA and other Western countries. Lipoproteins that contain apolipoprotein (apo) B-100 convey lipids into the artery wall. These are low-density (LDL), intermediate-density (IDL), very-low-density (VLDL), and lipoprotein(a) (Lp[a]). Remnant lipoproteins formed during the catabolism of chylomicrons that contain the B-48 protein (apo B-48) can also enter the artery wall, contributing to atherosclerosis.

Cellular components in atherosclerotic plaques (atheromas) include foam cells, which are transformed macrophages, and smooth muscle cells filled with cholesteryl esters. These cellular alterations result from endocytosis of modified lipoproteins via at least four species of scavenger receptors. Chemical modification of lipoproteins by free radicals creates ligands for these receptors. The atheroma grows with the accumulation of foam cells, collagen, fibrin, and frequently calcium. Whereas such lesions can slowly occlude coronary vessels, clinical symptoms are more frequently precipitated by rupture of unstable atheromatous plaques, leading to activation of platelets and formation of occlusive thrombi.

Although treatment of hyperlipidemia can cause slow physical regression of plaques, the well-documented reduction in acute coronary events that follows vigorous lipid-lowering treatment is attributable chiefly to mitigation of the inflammatory activity of macrophages and is evident within 2–3 months after starting therapy.

High-density lipoproteins (HDL) exert several antiatherogenic effects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. Low levels of HDL (hypoalphalipoproteinemia) are an independent risk factor for atherosclerotic disease and thus ...

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